In our previous studies of adults with mental retardation (MR) as part of the Program Project Grant, we have investigated the descriptive epidemiology of dementia including the incidence and prevalence of functional changes and dementia, and the determination of risk factors for dementia. As part of this research we have made several key observations among participants with Down syndrome (DS): (a) there was a strong association between high total cholesterol levels and earlier age at onset of dementia, (b) the Apolipoprotein E (APOE) epsilon 4 allele was associated with increased risk for dementia, (e) dementia was associated with higher levels of Abeta1-42, and (d) lower levels of high density lipoprotein cholesterol was associated with higher levels of Abeta1-40 and Abeta1-42. Recent research reports have indicated that in the general population, there is an interaction among APOE genotype, serum total cholesterol level, and risk for AD. Risk for AD is increased in adults with the APOE epsilon4 allele. The epsilon4 allele is associated with greater neural accumulation ofbeta-amyloid protein in the elderly and with high serum levels of total cholesterol in adults with AD. Risk for AD is decreased in those with the APOE epsilon2 allele and among those with a history of statin use. Subproject 1 will investigate the influence of serum cholesterol levels, serum amyloid-beta peptide Abeta 1-40/Abetal-42 levels, APOE genotype, and gender on age at onset and risk for Alzheimer's disease (AD) in 338 adults with DS over the next five years. We will determine the association between historical and current total cholesterol levels, APOE genotype, gender and age at onset and risk for AD. We will determine whether age at onset and risk for AD is associated with increases in plasma amyloid peptides A beta 1-40 and A beta1-42, and whether these increases will be related to APOE genotype, gender and total cholesterol levels. Finally, we will determine the association between historical and current statin use and age at onset and risk for AD.